Trelstar LA 11.25Mg for Injectable Suspension Triptorelin Pamoate for Injectable Suspension

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TrelstarTM LA 11.25mg TM brand of triptorelin pamoate Trelstar LA 11.25mg for injectable suspension triptorelin pamoate for injectable suspension

administration, there is a transient surge in circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol (see ADVERSE REACTIONS). After chronic and continuous administration, usually 2 to 4 weeks after initiation of therapy, a sustained decrease in LH and FSH secretion and marked reduction of testicular and ovarian steroidogenesis is observed. In men, a reduction of serum testosterone concentration to a level typically seen in surgically castrated men is obtained. Consequently, the result is that tissues and functions that depend on these hormones for maintenance become quiescent. These effects are usually reversible after cessation of therapy. Following a single intramuscular (IM) injection of TRELSTARTM LA to men with advanced prostate cancer, serum testosterone levels first increased, peaking on days 2-3, and declined thereafter to low levels

LA 11.25 mg by weeks 3-4. TM Pharmacokinetics triptorelin pamoate Results of pharmacokinetic investigations conducted in healthy for injectable suspension 0818917000

Trelstar men indicate that after intravenous (IV) bolus administration, triptorelin is distributed and eliminated according to a 3-compartment model and corresponding half-lives are approximately 6 minutes, 45 minutes, and 3 hours. Absorption: Triptorelin pamoate is not active when given orally. The pharmacokinetic parameters following a single IM injection of TM

LA 11.25 mg 11.25 mg of TRELSTAR LA to 13 patients with prostate cancer are

TM listed in Table 1. Triptorelin did not accumulate over 9 months of treat-

triptorelin pamoate ment.

for injectable suspension 0818917000

Trelstar TABLE 1. PHARMACOKINETIC PARAMETERS (MEAN ± SD) FOLLOWING INTRAMUSCULAR ADMINISTRATION OF TRELSTARTM LA TO PATIENTS WITH PROSTATE CANCER DESCRIPTION Dose C T AUC TRELSTARTM LA contains a pamoate salt of triptorelin, and trip- max(0-85d) max(1-85d) (1-85d) (No. of subjects) (ng/mL) (h) (h·ng/mL) torelin is a synthetic decapeptide agonist analog of luteinizing hormone releasing hormone (LHRH or GnRH) with greater potency than 11.25 mg 38.5 ± 10.5 2.9 ± 1.3 2268.0 ± 444.6 the naturally occurring LHRH. The chemical name of triptorelin (n=13) pamoate is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl- D-tryptophyl-L-leucyl-L-arginyl-L-prolylglycine amide (pamoate salt); Distribution: The volume of distribution following a single IV bolus dose of 0.5 mg of triptorelin peptide was 30-33 L in healthy male vol- the empirical formula is C64H82N18O13 · C23H16O6 and the molecular weight is 1699.9. The structural formula is shown below. unteers. There is no evidence that triptorelin, at clinically relevant con- centrations, binds to plasma proteins. H2N NH Metabolism: The metabolism of triptorelin in humans is unknown, HN but is unlikely to involve hepatic microsomal enzymes (cytochrome

CH3 P-450). However, the effect of triptorelin on the activity of other drug HO + N NH HN H3C 3 metabolizing enzymes is unknown. Thus far, no metabolites of trip- N H HO N NH N H O HN N H O torelin have been identified. Pharmacokinetic data suggest that C-ter- N N H O N H O H O minal fragments produced by tissue degradation are either completely O N O ¥ pamoic acid N H N H O C H O H O 23 16 6 degraded in the tissues, or rapidly degraded in plasma, or cleared by O O the kidneys. TRELSTARTM LA is a sterile, lyophilized biodegradable microgran- Excretion: Triptorelin is eliminated by both the liver and the kid- ule formulation supplied as a single-dose vial containing triptorelin neys. Following IV administration of 0.5 mg triptorelin peptide to pamoate (11.25 mg as the peptide base), 145 mg poly d,l-lactide-co- 6 healthy male volunteers with a creatinine clearance of 149.9 mL/min, glycolide, 85 mg mannitol USP, 30 mg carboxymethylcellulose sodium 41.7% of the dose was excreted in urine as intact peptide with a total USP, 2 mg polysorbate 80 NF. When 2 mL sterile water for injection is triptorelin clearance of 211.9 mL/min. This percentage increased to added to the vial containing TRELSTARTM LA and mixed, a suspension 62.3% in patients with liver disease who have a lower creatinine is formed which is intended as an intramuscular injection to be admin- clearance (89.9 mL/min). It has also been observed that the non- istered every 84 days (ie, every 12 weeks). TRELSTARTM LA is available renal clearance of triptorelin (patient anuric, Clcreat =0) was in 2 packaging configurations: (a) TRELSTARTM LA vial alone or (b) 76.2 mL/min, thus indicating that the nonrenal elimination of trip- TRELSTARTM LA vial plus a separate pre-filled syringe that contains torelin is mainly dependent on the liver (see Special Populations). 2 mL of sterile water for injection, USP (DebioclipTM). Special Populations: Renal and Hepatic Impairment: After an IV bolus injection of 0.5 mg CLINICAL PHARMACOLOGY triptorelin peptide, the two distribution half-lives were unaffected by Mechanism of Action renal and hepatic impairment, but renal insufficiency led to a decrease Triptorelin is a potent inhibitor of gonadotropin secretion when in total triptorelin clearance proportional to the decrease in creatinine given continuously and in therapeutic doses. Following the first clearance as well as an increase in volume of distribution and TrelstarTM LA 11.25mg TrelstarTM LA 11.25mg brand of triptorelin pamoate brand of triptorelin pamoate for injectable suspension for injectable suspension

TABLE 2. PHARMACOKINETIC PARAMETERS (MEAN ±SD) IN HEALTHY VOLUNTEERS AND SPECIAL POPULATIONS

1 Cmax AUCinf Clp Clrenal t /2 Clcreat Group (ng/mL) (h·ng/mL) (mL/min) (mL/min) (h) (mL/min)

6 healthy male 48.2 36.1 211.9 90.6 2.81 149.9 volunteers ±11.8 ±5.8 ±31.6 ±35.3 ±1.21 ±7.3

6 males with moderate 45.6 69.9 120.0 23.3 6.56 39.7 renal impairment ±20.5 ±24.6 ±45.0 ±17.6 ±1.25 ±22.5

6 males with severe 46.5 88.0 88.6 4.3 7.65 8.9 renal impairment ±14.0 ±18.4 ±19.7 ±2.9 ±1.25 ±6.0

6 males with liver 54.1 131.9 57.8 35.9 7.58 89.9 disease ±5.3 ±18.1 ±8.0 ±5.0 ±1.17 ±15.1 consequently an increase in elimination half-life (Table 2). The WARNINGS decrease in triptorelin clearance was more pronounced in subjects with Rare reports of anaphylactic shock and angioedema related to trip- liver insufficiency, but the half-life was prolonged similarly in subjects torelin administration have been reported. In the event of a reaction, with renal insufficiency, since the volume of distribution was only min- therapy with TRELSTARTM LA should be discontinued immediately and imally increased. Patients with renal or hepatic impairment had 2- to the appropriate supportive and symptomatic care should be adminis- 4-fold higher exposure (AUC values) than young healthy males. tered. Age and Race: The effects of age and race on triptorelin pharma- Initially, triptorelin, like other LHRH agonists, causes a transient cokinetics have not been systematically studied. However, pharma- increase in serum testosterone levels. As a result, isolated cases of cokinetic data obtained in young healthy male volunteers aged 20 to worsening of signs and symptoms of prostate cancer during the first 22 years with an elevated creatinine clearance (approximately weeks of treatment have been reported with LHRH agonists. Patients 150 mL/min) indicates that triptorelin was eliminated twice as fast in may experience worsening of symptoms or onset of new symptoms, this young population (see Special Populations, Renal and Hepatic including bone pain, neuropathy, hematuria, or urethral or bladder Impairment) as compared to patients with moderate renal insuffi- outlet obstruction. Cases of spinal cord compression, which may con- ciency. This is related to the fact that triptorelin clearance is partly cor- tribute to paralysis with or without fatal complications, have been related to total creatinine clearance, which is well known to decrease reported with LHRH agonists. with age. If spinal cord compression or renal impairment develops, standard Pharmacokinetic Drug-Drug Interactions: No pharmacokinetic drug- treatment of these complications should be instituted, and in extreme drug interaction studies have been conducted with triptorelin (See cases an immediate orchiectomy considered. PRECAUTIONS, Drug Interactions). PRECAUTIONS Clinical Trials General: Patients with metastatic vertebral lesions and/or with TRELSTARTM LA was studied in a randomized, active control trial of upper or lower urinary tract obstruction should be closely observed dur- 346 men with advanced prostate cancer in South Africa. The clinical ing the first few weeks of therapy (see WARNINGS). Hypersensitivity trial population consisted of 48% Caucasian, 38% Black, and 15% and anaphylactic reactions have been reported with triptorelin as Other. Men were between 45 and 96 years of age (71 mean). Patients with other LHRH agonists (see CONTRAINDICATIONS and WARNINGS). received either TRELSTARTM LA ( n = 174) every 84 days for a total of Laboratory Tests: Response to TRELSTARTM LA should be moni- up to 3 doses (maximum treatment period of 252 days) or TrelstarTM tored by measuring serum levels of testosterone and prostate-specific Depot (n = 172) every 28 days for a total of up to 9 doses. The primary antigen. Testosterone levels should be measured immediately prior to efficacy endpoints were both achievement of castration by Day 29 and or immediately after dosing. maintenance of castration from Day 57 through Day 253. Drug Interactions: No drug-drug interaction studies involving Castration levels of serum testosterone (≤1.735 nmol/L) were triptorelin have been conducted. In the absence of relevant data and achieved at Day 29 in 167 of 171 (97.7%) of patients treated with as a precaution, hyperprolactinemic drugs should not be prescribed TRELSTARTM LA. concomitantly with TRELSTARTM LA since hyperprolactinemia reduces Maintenance of castration levels of serum testosterone from Day 57 the number of pituitary GnRH receptors. through Day 253 was found in 94.4% of patients treated with Drug/Laboratory Test Interactions: Chronic or continuous admin- TRELSTARTM LA. istration of triptorelin in therapeutic doses results in suppression of the pituitary-gonadal axis. Diagnostic tests of the pituitary-gonadal func- INDICATIONS AND USAGE tion conducted during treatment and after cessation of therapy may TRELSTARTM LA is indicated in the palliative treatment of advanced therefore be misleading. prostate cancer. It offers an alternative treatment for prostate cancer Pregnancy, Teratogenic Effects: Pregnancy Category X (see when orchiectomy or estrogen administration are either not indi- CONTRAINDICATIONS). TRELSTARTM LA is contraindicated in women cated or unacceptable to the patient. who are or may become pregnant while receiving the drug. Studies in CONTRAINDICATIONS pregnant rats administered triptorelin at doses of 2, 10, and TRELSTARTM LA is contraindicated in individuals with a known 100 mcg/kg/day (approximately equivalent to 0.2, 0.8, and 8 times the hypersensitivity to triptorelin or any other component of the product, recommended human therapeutic dose based on body surface area) other LHRH agonists or LHRH. during the period of organogenesis displayed maternal toxicity and TRELSTARTM LA is contraindicated in women who are or may embryotoxicity, but no fetotoxicity or teratogenicity. Similarly, no become pregnant while receiving the drug. TRELSTARTM LA may cause teratogenic effects were observed when mice were administered doses fetal harm when administered to a pregnant woman. of 2, 20, and 200 mcg/kg/day (approximately equivalent to 0.1, 0.7, TrelstarTM LA 11.25mg TrelstarTM LA 11.25mg brand of triptorelin pamoate brand of triptorelin pamoate for injectable suspension for injectable suspension

and 7 times the recommended human therapeutic dose based on TABLE 3. TREATMENT-RELATED ADVERSE EVENTS REPORTED BY 1% body surface area). If this drug is used during pregnancy or if the OR MORE OF PATIENTS DURING TREATMENT WITH TRELSTARTM LA patient becomes pregnant while taking this drug, she should be TRELSTARTM LA apprised of the potential hazard to the fetus (see PRECAUTIONS, and N=174 Pregnancy). Carcinogenesis, Mutagenesis, Impairment of Fertility: In rats, N % doses of 120, 600, and 3000 mcg/kg given every 28 days (approxi- Application Site mately 0.3, 2, and 8 times the recommended human therapeutic dose Injection site pain 7 4.0 based on body surface area) resulted in increased mortality with a drug Body As A Whole treatment period of 13-19 months. The incidence of benign and malig- Hot flushes* 127 73.0 nant pituitary tumors and histiosarcomas were increased in a dose Leg pain 9 5.2 related manner. No oncogenic effect was observed in mice adminis- Pain 6 3.4 tered triptorelin for 18 months at doses up to 6000 mcg/kg every Back pain 5 2.9 28 days (approximately 8 times the human therapeutic dose based on Fatigue 4 2.3 body surface area). Chest pain 3 1.7 Asthenia 2 1.1 Mutagenicity studies performed with triptorelin using bacterial Peripheral edema 2 1.1 and mammalian systems (in vitro Ames test and chromosomal aber- ration test in CHO cells and an in vivo mouse micronucleus test) pro- Cardiovascular vided no evidence of mutagenic potential. Hypertension 7 4.0 After 60 days of treatment followed by a minimum of four Dependent edema 4 2.3 estrus cycles prior to mating, triptorelin, at doses of 2, 20, and Central and Peripheral 200 mcg/kg/day in saline (approximately 0.2, 2.0, and 16 times the rec- Nervous System ommended human therapeutic dose based on body surface area) or Headache 12 6.9 Dizziness 5 2.9 20 mcg/kg/day in slow release microspheres, had no effect on the fer- Leg cramps 3 1.7 tility or general reproductive performance of female rats. Treatment did not elicit embryotoxicity, teratogenicity, or any effects on the Endocrine Breast pain 4 2.3 development of the offspring (F1 generation) or their reproductive performance. Gynecomastia 3 1.7 No studies were conducted to assess the effect of triptorelin on male Gastrointestinal fertility. Nausea 5 2.9 Geriatric Use: Prostate cancer occurs primarily in an older patient Constipation 3 1.7 Dyspepsia 3 1.7 population. Clinical studies with TRELSTARTM LA have been conducted ≥ Diarrhea 2 1.1 primarily in patients 65 years old. Abdominal pain 2 1.1 Use in Women: TRELSTARTM LA has not been studied in women and is not indicated for use in women. Liver and Biliary System Abnormal hepatic function 2 1.1 Nursing Mothers: It is not known whether TRELSTARTM LA is excreted in human milk. Because many drugs are excreted in human Metabolic and Nutritional milk and because the effects of TRELSTARTM LA on lactation and/or the Edema in legs 11 6.3 breastfed child have not been determined, TRELSTARTM LA should not Increased alkaline phosphatase 3 1.7 be used by nursing mothers. Musculoskeletal System Pediatric Use: TRELSTARTM LA has not been studied in pediatric Skeletal pain 23 13.2 patients and is not indicated for use in pediatric patients. Arthralgia 4 2.3 Myalgia 2 1.1 ADVERSE REACTIONS Psychiatric In the majority of patients, testosterone levels increased above Decreased libido* 4 2.3 baseline during the first week following the initial injection, declin- Impotence* 4 2.3 ing thereafter to baseline levels or below by the end of the second week Insomnia 3 1.7 of treatment. The transient increase in testosterone levels may be asso- Anorexia 3 1.7 ciated with temporary worsening of disease signs and symptoms, Respiratory System including bone pain, hematuria, and bladder outlet obstruction. Coughing 3 1.7 Isolated cases of spinal cord compression with weakness or paralysis Dyspnea 2 1.1 of the lower extremities have occurred (see WARNINGS). Pharyngitis 2 1.1 In a controlled, comparative clinical trial, the following adverse reac- Skin and Appendages tions were reported to have a possible or probable relationship to ther- Rash 3 1.7 apy as ascribed by the treating physician in 1% or more of the patients receiving triptorelin (Table 3). Often, causality is difficult to assess in Urinary System patients with metastatic prostate cancer. Reactions considered not Dysuria 8 4.6 drug-related or unlikely to be related are excluded. Urinary retention 2 1.1 Changes in Laboratory Values During Treatment: The following Vision Disorders abnormalities in laboratory values not present at baseline were Eye pain 2 1.1 observed in 10% or more of patients at the Day 253 visit: decreased Conjunctivitis 2 1.1 hemoglobin and RBC count and increased glucose, BUN, SGOT, SGPT, * Expected pharmacologic consequences of testosterone suppression. and alkaline phosphatase. The relationship of these changes to drug treatment is difficult to assess in this population. TrelstarTM LA 11.25mg TrelstarTM LA 11.25mg brand of triptorelin pamoate brand of triptorelin pamoate for injectable suspension for injectable suspension

OVERDOSAGE pamoate microgranules equivalent to 11.25 mg of triptorelin peptide There is no experience of overdosage in clinical trials. In single base, incorporated in a biodegradable copolymer of lactic and glycolic dose toxicity studies in mice and rats, the subcutaneous LD50 of trip- acids, and a pre-filled syringe containing 2 mL sterile water for injec- torelin was 400 mg/kg in mice and 250 mg/kg in rats, approximately tion, USP. 7000 and 4000 times, respectively, the usual human dose. If over- When mixed with sterile water for injection, TRELSTARTM LA is dosage occurs however, therapy should be discontinued immediately administered every 84 days as a single intramuscular injection. and the appropriate supportive and symptomatic treatment adminis- Store at 20-25°C (68-77°F); excursions permitted to 15-30°C tered. (59-86°F) [see USP Controlled Room Temperature]. Do not freeze. DOSAGE AND ADMINISTRATION TRELSTARTM LA Must Be Administered Under the Supervision of a Physician. The recommended dose of TRELSTARTM LA is 11.25 mg incorporated in a long acting formulation administered every 84 days as a single intramuscular injection administered in either buttock. The lyophilized microgranules are to be reconstituted in sterile water. No other diluent should be used. Reconstitute in accord with the following: For TRELSTARTM LA: 1. Using a syringe fitted with a sterile 20-gauge needle, withdraw 2 mL sterile water for injection, USP, and after removing the flip-off seal from the vial, inject into the vial. 2. Shake well to thoroughly disperse particles to obtain a uniform suspension. The suspension will appear milky. 3. Slowly withdraw the entire contents of the reconstituted suspension into the syringe. 4. Inject the patient in either buttock with the contents of the syringe. The suspension should be discarded if not used immediately after reconstitution. For the TRELSTARTM LA DebioclipTM single-dose delivery system: %only 1. Remove the Tyvek® cover from the blister pack. 2. Remove the vial from its case. Remove the flip-off vial cover U.S. Patent No.: 5,134,122; 5,225,205; 5,192,741.

and place the vial in the vertical position. ➞ TM - Trademark 3. Hold the lower part of the TRELSTARTM LA DebioclipTM and press it firmly onto the top Manufactured for: of the vial (See Figure). Pharmacia & Upjohn Company 4. Hold firmly the syringe barrel. Push the Kalamazoo, MI 49001, USA finger grip in the direction of the vial as far by: as it will go (until you hear a click). Debio RP 5. Take the plunger rod and screw it into the CH-1920 Martigny, Switzerland upper joint of the syringe. 6. Press the plunger rod to release the con- 818 917 000 tents of the syringe into the vial. August 2001 692166 7. Mix and withdraw the contents of the vial into the syringe. 8. Remove the syringe from the TRELSTARTM LA DebioclipTM. 9. Inject the patient in either buttock with the contents of the syringe. The suspension should be discarded if not used immediately after reconstitution. As with other drugs administered by intramuscular injection, the injection site should be altered periodically. HOW SUPPLIED TRELSTARTM LA (NDC 0009-5215-01) is supplied in a single-dose vial with a flip-off seal containing sterile lyophilized triptorelin pamoate microgranules equivalent to 11.25 mg triptorelin peptide base, incorporated in a biodegradable copolymer of lactic and glycolic acids. A single dose vial of TRELSTARTM LA contains triptorelin pamoate (11.25 mg as peptide base units), poly-d,l-lactide-co-glycolide, (145 mg), mannitol, USP (85 mg), carboxymethylcellulose sodium, USP (30 mg), and polysorbate 80, NF (2 mg). TRELSTARTM LA (NDC 0009-5216-01) is also supplied in the TRELSTARTM LA DebioclipTM single-dose delivery system consisting of a vial with a flip-off seal containing sterile lyophilized triptorelin